It has been established that various piperidinoalkanol compounds are useful as antihistamines, antiallergy agents and bronchodilators as disclosed in U.S. Pat. Nos. 3,878,217, 4,254,129 and 4,285,957. Several examples of formulations of these various piperidinoalkanol compounds are described below.
J. Domet and D. Shah describe in U.S. Pat. No. 4,929,605, a pharmaceutical composition in solid unit dosage form, comprising, a therapeutically effective amount of a piperidinoalkanol compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable nonionic or cationic surfactant in an amount of from about 0.1% to about 6% by weight of the composition, and a pharmaceutically acceptable carbonate salt in an amount of from about 2% to about 50% by weight of the composition.
N. Webb and G. Hammer describe in U.S. Pat. No. 4,996,061, a pharmaceutical composition in the form of a multiple-compression tablet comprising a discrete zone made from a formulation which provides sustained-release of a therapeutically effective decongestant amount of a sympathomimetic drug and a discrete zone made from a different formulation which provides immediate release of a therapeutically effective antihistaminic amount of a piperidinoalkanol and, optionally, a therapeutically effective decongestant amount of a sympathomimetic drug.
H. Schock, et al. describe in U.S. Pat. No. 4,999,226 a multi-layered tablet containing an ibuprofen layer, a piperidinoalkanol antihistamine layer, and a layer or layers containing conventional pharmaceutical excipients which is interspersed between the ibuprofen and piperidinoalkanol layer and serves to physically separate them. It was disclosed by Schock et al. that attempts to formulate a two-layered tablet failed as a result of chemical degradation of the piperidinoalkanol in the presence of ibuprofen. In addition, attempts to retard this rate of degradation using anti-oxidants also failed.
T. Ortyl, et al. disclose in International Application No. WO 96/26726, published Sep. 6, 1996, a pharmaceutical composition in solid unit dosage form comprising a piperidinoalkanol compound and at least one inert ingredient.
A number of products are currently available for the treatment of the symptomatology associated with ailments such as the common cold, seasonal rhinitis, sinus headaches, sinusitis, etc., which contain multiple therapeutic agents. Many of these products contain an antihistamine in combination with a sympathomimetic decongestant. Such combination products are convenient for the patient since they allow the patient to obtain relief from numerous symptoms without taking multiple medications.
An attempt was made to formulate a multiple-compression tablet containing the sympathomimetic drug, pseudoephedrine hydrochloride in sustained release form with the piperidinoalkanol, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperdinyl]-1-hydroxybutyl]-.alpha.,.alp ha.-dimethylbenzeneacetic acid hydrochloride, in immediate release form using a formulation similar to that disclosed by N. Webb and G. Hammer in U.S. Pat. No. 4,996,061. However, this formulation failed as a result of unexpected and unacceptable cracking and unacceptable physical strength of the tablets on final compression.
In addition, an attempt was made to prepare a single compression tablet wherein pseudoephedrine hydrochloride sustained release beads and an immediate release form of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperdinyl]-1-hydroxybutyl]-.alpha.,.alp ha.-dimethylbenzeneacetic acid hydrochloride were combined in a single layer tablet. However, this formulation also failed as some of the samples collected during tablet compression and tested for content uniformity did not meet United States Pharmacopeia (USP) requirements.
An object of the present invention is to provide a pharmaceutical composition in oral dosage form as a bilayer tablet which provides immediate release of a piperidinoalkanol compound and sustained release of a sympathomimetic drug that exhibits acceptable bioavailability of each compound. An additional object of the invention is to provide a pharmaceutical composition in bilayer tablet form of high integrity consisting of an immediate release form of a piperidinoalkanol compound and a sustained release form of a sympathomimetic drug, such that the tablet resists cracking on standing, has acceptable physical strength and provides acceptable content uniformity which meets USP requirements. A further object of the present invention is to provide a bilayer tablet which exhibits a dissolution profile of the piperidinoalkanol which is similar to that of ALLEGRA.RTM. 60 mg capsules and a dissolution profile of the sympathomimetic drug which is slower than that of SUDAFED.RTM. 120 mg tablets.
A novel pharmaceutical composition in the form of a bilayer tablet has now been found which provides efficient and immediate absorption, and bioavailability of a piperidinoalkanol, such as 4-[4-[4-(hydroxydiphenylmethyl)-1-piperdinyl]-1-hydroxybutyl]-.alpha.,.alp ha.-dimethylbenzeneacetic acid hydrochloride, and efficient sustained release and bioavailability of a sympathomimetic drug, such as pseudoephedrine hydrochloride after oral administration thereof. In addition, the novel bilayer tablet of the present invention exhibits acceptable content uniformity under USP requirements, resists cracking on standing and has acceptable physical strength. Furthermore, the novel bilayer tablet of the present invention provides a dissolution profile of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperdinyl]-1-hydroxybutyl]-.alpha.,.alp ha.-dimethylbenzeneacetic acid hydrochloride which is similar to that for ALLEGRA.RTM. 60 mg capsules and a dissolution profile for pseudoephedrine hydrochloride which is slower than that for SUDAFED 12 HOUR.RTM. 120 mg tablets.